The overall goal of this proposal is to establish Dr. Shilpa Vyas-Read as an independent investigator in the fields of alveolar epithelial biology, oxidative stress and lung repair. Dr. Vyas-Read's long term goal of identifying novel mechanisms that contribute to aberrant alveolar epithelial repair in patients with interstitial lung disease can only be achieved by establishing a rigorous curriculum that enhances her technical expertise, increases her didactic knowledge of cellular processes, and allows for scientific dialogue among well- established lung biologists. Dr. Vyas-Read has chosen to perform her research in the laboratory of her primary mentor, Dr. Lou Ann Brown. Dr. Brown is an expert in the fields of lung biology and oxidative stress and has mentored several investigators to independence. Additionally, each of the members of Dr. Vyas-Read's Advisory Committee has a unique expertise in the areas to be interrogated in the research plan: oxidative stress (Dr. T. Gauthier), NADPH oxidases (Dr. K. Griendling and Dr. M. Hart) and epithelial to mesenchymal transition (Dr. A.Stecenko). In addition to structured scientific oversight meetings, Dr. Vyas-Read has developed a curriculum designed to increase her knowledge of cell biology through the Graduate Division of Biologic and Biomedical Sciences. To increase her scientific discourse, Dr. Vyas-Read has identified scientific seminars on campus and national meetings that she will attend. The research plan stems from the exciting preliminary data that reactive oxygen species (ROS) induce epithelial-to-mesenchymal transition (EMT) in alveolar epithelial cells and that antioxidants, such as glutathione, can attenuate this transition. EMT is the pathway by which type II cells, instead of completing normal lung repair following injury, transition into extracellular matrix-generating mesenchymal cells. Lung specimens from patients with interstitial lung disease and animal models have demonstrated that EMT is a significant source of myofibroblasts in the chronically injured lung. Based on her preliminary data, Dr. Vyas- Read will investigate if 1) NADPH oxidase-derived ROS promote EMT, 2) if ROS induce alveolar EMT through SNAI1 transcription factors and 3) how glutathione and its regulator, Nrf-2, attenuate alveolar EMT. This research proposal will elucidate the mechanisms by which oxidant stress and antioxidant depletion promote EMT of alveolar epithelial cells and contribute to aberrant repair processes. The results of these investigations will contribute to our understanding of the mechanisms that regulate alveolar epithelial fate and may ultimately lead to the development of effective therapies for patients with interstitial lung diseases. The scientific guidance of experienced lung biologists, the comprehensive coursework, and the engaging seminars available at Emory University make it an ideal setting for these inquiries. Additionally, this proposal and the Mentored Clinical Scientist Research Career Development Award will lay the foundation for future investigations into alveolar epithelial cell biology and plasticity for Dr. Vyas-Read. PUBLIC HEALTH RELEVANCE: A mechanistic understanding of the pathogenesis of interstitial lung diseases may lead to the advent of effective therapies that improve outcome for affected patients. This proposal seeks to determine manner by which oxidative stress and antioxidant depletion promote abnormal lung repair and lead to fibrosis.